A population-based propensity score matching analysis of risk factors and the impact on survival associated with refusal of cancer-directed surgery in patients with prostate cancer

Cancer-directed surgeries (CDS) play a crucial role in prostate cancer (PCa) management along with possible survival and therapeutic benefits. However, barriers such as socioeconomic factors may affect patients’ decision of refusing recommended CDS. This study aimed to uncover risk factors and the impact on survival associated with CDS refusal. We retrospectively reviewed the Surveillance, Epidemiology, and End Results database for patients diagnosed with PCa between 2000 and 2019. Multiple sociodemographic and clinical characteristics were extracted to assess predictors for physicians’ surgical recommendations and patients’ surgical refusal, respectively. Propensity score matching was performed to balance the covariates. The impact of surgical refusal on mortality risk was also investigated. A total of 185,540 patients were included. The physician’s recommendation of CDS was significantly influenced by the patient’s age, race, income, home location, diagnosis year, Gleason score, prostate-specific antigen (PSA), and TNM stage. About 5.6% PCa patients refused CDS, most of whom were older, non-White race, lack of partners, living outside of metropolitan areas, with higher PSA or lower clinical TNM stage. Patients who refused CDS had an increased risk of cancer-specific mortality and overall mortality than those who performed CDS. Physicians may weigh a host of sociodemographic and clinical factors prior to making a CDS recommendation. Patients’ refusal of recommended CDS affected survival and was potentially modifiable by certain sociodemographic factors. Physicians should fully consider the hindrances behind patients’ CDS refusal to improve patient-doctor shared decision-making, guide patients toward the best alternative and achieve better outcomes.


Study population and variables
Sociodemographic and clinical characteristics of each patient were extracted for analysis as in our previous study 15 .A brief description of these variables is presented as follows: age at diagnosis, year of diagnosis, race (black (African American), white (Caucasian), others (American Indian/AK Native, Asian/Pacific Islander)), marital status (married, single, and unknown), annual household income (< $65 000, ≥ $65 000, and unknown), residential location (large city, small city and missing value), Gleason score (≤ 6, = 7, and 8-10), serum prostatespecific antigen (PSA) value (≤ 0.10 ng/ml, ≥ 98.00 ng/ml, others), systemic therapy (yes, no, unknown) and longitudinal follow-up of vital status.The PCa stage was identified by the American Joint Committee on Cancer Tumor-Node-Metastasis (AJCC-TNM) stage, seventh edition.
To identify the variables affecting physicians' decisions, we set up a case-control cohort between patients with recommended CDS and not.According to SEER Program Coding and Staging Manual (https:// seer.cancer.gov/ tools/ codin gmanu als/), CDS-recommended (CDSR) was defined as the following items: surgery performed, surgery unknown if performed or recommended but not performed due to unknown reason, and surgery recommended but not performed due to patient's, patient's family member's or the patient's guardian's refusal.CDSnot recommended (CDSnR) represented those patients not recommended to undergo CDS by medical service providers, regardless of whether the patients underwent the surgery or not.
To determine the variables contributing to the patient's refusal of recommended surgery, another grouped comparison was conducted between those who underwent CDS (CDS accepted = CDSA) or not (CDS not accepted = CDSnA).CDSA was defined as patient accepted surgery treatment (surgery performed).Moreover, cancer-specific mortality (CSM) and overall mortality (OM) were collected to evaluate the benefit of CDSA for PCa patients."SEER cause-specific death classification" and "vital status recode" in the database were used to calculate CSM and OM, respectively.

Statistics analysis
The statistical analyses consisted of three steps.Firstly, nonparametric independent-sample tests were used to compare two cohort groups (CDSR vs CDSnR, CDSA vs CDSnA) before and after propensity score matching (PSM).PSM was performed to adjust differences in potential covariates by a 1:1 matching ratio.A subset of variables was chosen for PSM matching: age, diagnosis year, race, marital status, income, and home location.PSA, GS, and AJCC stages were not adopted for matching due to > 50% missing records.Secondly, binary logistic regression in univariate and multivariable analyses were applied to determine the variables associated with CDS recommendation or CDS refusal, respectively.Thirdly, the Kaplan-Meier method and multivariable Cox

Ethical approval
This study was exempt from local research ethics committee approval, considering that SEER data were deidentified and publicly available for research use.

Demographic and clinical characteristics of patients with or without CDS recommendation
A total of 193,632 PCa cases diagnosed between 2000 and 2019 were extracted from the database.After considering inclusion and exclusion criteria, 185,540 cases were finally included for analysis.The median age at diagnosis for the total study population was 60 to 69 years old (40.2%).Of these patients, 94,964 cases (51.2%) were recommended CDS and 90,576 (48.8%) were determined not to be surgical candidates (Table 1).The comparison without PSM showed significant differences in multiple covariates (age, race, partner, income, home location, diagnosis year, Gleason score, PSA, clinical M stage, chemotherapy, radiotherapy, and system therapy) between CDSR and CDSnR groups (all p < 0.05).After PSM by 1:1 ratio, 59,833 cases were selected for each group.Significant differences could still be found in Gleason score, PSA, clinical TNM stage, chemotherapy, radiotherapy and system therapy between the two groups (all p < 0.05).

Demographic and clinical characteristics of patients with or without accepted CDS
Of the entire cohort, 74,074 cases were involved for comparison.The median age range was 60 to 69 years old (39.0%).69,926 (94.4%) patients accepted CDS but 4148 (5.6%) refused CDS (Table 3).Before PSM, the comparison between CDSA and CDSnA showed significant differences in diverse covariates (age, race, partner, home location, diagnosis year, PSA, clinical M stage, radiotherapy and system therapy) (all p < 0.05).After PSM, 3869 cases were left in each group for comparison.Significant differences remained in PSA, chemotherapy, radiotherapy and system therapy when comparing the two groups (all p < 0.05).

Factors predicting patient's refusal of CDS treatment
As shown by univariate analysis (Table 4), patients refusing CDS treatment were more likely to be older, non-White race, lack partners, living outside of metropolitan area, higher PSA, lower clinical N and M stage and were diagnosed before the 2009 year (all p < 0.05).However, multivariate analysis indicated no factors significantly related to patients' refusal of CDS treatment.

Refusal of CDS and Mortality
To further investigate the impact of the decision to refuse surgery on survival, Kaplan-Meier analysis and multivariable Cox proportional hazard models were adopted.As shown in Kaplan-Meier plots (Fig. 2A,B), significantly lower rates of CSM and OM (both p < 0.05) were determined in the CDSA group after 120 months.Cox proportional hazard models with or without PSM supported that CDS refusal could significantly increase the risk of CSM (hazard ratio, 0.54; 95% confidence interval, 0.49-0.59)and OM (hazard ratio, 0.59; 95% confidence interval, 0.56-0.61),respectively (Table 5).The Forest plot presented the subgroup analysis for CDSA vs CDSnA in CSM and OM, respectively (Fig. 3).The results demonstrated that patients refusing CDS obtained significantly poorer prognoses than those accepting CDS, particularly across age and diagnosis year subgroups.Younger patients diagnosed between 2010 and 2019 were more likely to have lower rates of CSM and OM.

Discussion
Our study presented one of the largest pooled analyses of patients with PCa and highlighted the identifiable factors to predict the likelihood of a physician's CDS recommendation and a patient's CDS refusal.Particularly, we demonstrated that CDS refusal was associated with increased odds of CSM and OM.A better understanding of the effects of sociodemographic factors may enable to improve patients' satisfaction, surgical utilization and treatment outcomes.The decision to undergo CDS in PCa patients is personal and complex and undoubtedly, patients have full rights in their decision-making process.However, our results revealed that physicians' recommendation of CDS could strongly affect patients' final choices.Univariate analysis in this study demonstrated that physician's recommendation of CDS was determined by the patient's age, race, income, home location, diagnosis year, Gleason score, PSA and TNM stage.However, after multivariate analysis, only age, Gleason score, and clinical T and M stages were significantly associated with the increased recommendation of CDS treatment.In other words, physicians may only factor patients' medical situation into their CDS recommendation and this decision process was not affected by patients' socioeconomic factors.This finding was compatible with previous literature.Scherr et al. reported that PCa patients' treatment decisions were chiefly decided by their urologists' recommendations, which in turn were driven by medical factors (age, Gleason score, etc.) without patients' preferences 16 .In addition, PCa patients diagnosed by urologists, rather than radiation oncologists, greatly preferred to receive up-front treatment such as CDS 10 .Different specialty types could lead to disparities in treatment outcomes in PCa patients 11 .Given the centrality of physicians' recommendations in the decision-making process, physicians should strive for effective communication with the candidates and emphasize the important role of CDS in managing PCa.www.nature.com/scientificreports/CDS, such as radical prostatectomy and cytotherapeutic ablation, could serve as an established pillar of therapeutic options for PCa in particular localized ones 3,4 .When facing the selection of surgical interventions, patients undeniably weigh the potential tradeoffs between benefits and burdens.Despite the potential lifesaving or life-prolonging effect of CDS, a portion of PCa patients may still refuse to receive CDS treatments due to multiple reasons.Our study reported that about 5.6% PCa patients refused CDS, most of whom were older, non-White race, lack of partners, living outside of metropolitan areas.Particularly, PCa patients with higher PSA or lower clinical TNM stage proposed CDS refusal.These results were in parallel with prior studies.Islam et al. found that about 3.9% PCa patients refused the suggested surgery and those black, single, Medicaid/Medicarecovered, or early-stage ones had significantly increased odds of refusal rate 12 .Xu and colleagues reported a relatively lower refusal rate (2.47%) of CDS in PCa patients and pointed out that black and Asian/Pacific Islander patients were more likely to refuse CDS than White ones 14 .Quiet similarly, a recent study by Dee et al. indicated that older age, black/Asian, noninsurance or Medicaid, community facility type and later year of diagnosis were associated with increased odds of locoregional treatment (i.e., surgery ) refusal in PCa patients 13 .The influence of sociodemographic factors on CDS refusal can also be found in other cancer treatments such as lung cancer 17 , colon cancer 18 , breast cancer 19 and so on.More attention should be paid to these factors that influence patients' treatment decisions.
Sociodemographic factors especially age, race, marital status and cancer stage could act as vital predictors for patients' CDS refusal due to nuanced and complex contributions.For instance, older patients may be more likely to refuse CDS due to a fear of a decrease in quality of life 7 , a perceived lack of social support 20 , an unaffordable surgical fee 21 , a group of comorbidities 22 , an existing communication gap between physicians 23 and so on.Besides, the high rate of CDS refusal in non-White populations might be attributed to greater distrust toward the healthcare system 24 , late lacking medical insurance 12 and different cultural competency 25 .Consequently, sociodemographic factors can play a crucial role in the decision of declining the CDS for PCa patients.Physicians, especially urologists, should fully consider the barriers behind patients' refusal of CDS to improve patients' satisfaction, surgical utilization, and treatment outcomes.
Of note, the most influential factors in PCa patients' treatment decisions were the perceptions of therapeutic efficacy and side effects, mainly derived from physicians' descriptions 26 .Our study revealed that PCa patients who refused CDS had an increased risk of death ( hazard ratio 0.54 in CSM and hazard ratio 0.59 in OM) than those who accepted.Consistently, Rapp et al. 's study identified an overall 1.60 higher mortality in PCa patients who refused CDS 7 .In other words, PCa patients could significantly benefit from CDS and achieve a longer survival time.Given surgery refusal increasing CSM, physicians should carefully and clearly inform PCa patients regarding their prognosis in case they are thinking of skipping surgical treatment.CDS may be a viable alternative option for those with locally advanced or even distant stages of PCa.www.nature.com/scientificreports/factors for analysis, such as PSA, Gleason score and TNM stage.Detailly, disease-related factors such as GS, PSA, and T stage was not adjusted with PSM in this study, which is a limitation to permit valid comparisons.Despite this, the main goal of this study is to uncover sociodemographic factors and their impacts on survival associated with cancer-directed surgeries refusal.The impacts of PSA, GS, and AJCC stages on survival time have been well discussed in studies [27][28][29] .Additionally, we did not perform subset analyses to identify whether CDS impacts on survival outcomes in GS 6 or ≤ T2 disease.GS 6 or ≤ T2 stage represents localised prostate cancer and CDS is one of the most effective treatments for this type of prostate cancer according to EAU guideline and other guidelines.These patients with CDS presented a longer survival time as supported by numerous studies 30,31 .In spite of these limitations, however, our present study was one of the largest SEER-based analysis to identify predictors for patients' CDS refusal and subsequent effect on cancer survival.One strength of this study was the application of a series of statistical analyses such as PSM to mitigate limitations.Notably, our study shined a spotlight on physicians' key role in patients' decision-making process, providing valuable information for patient-doctor relationships and communication.

Conclusions
In conclusion, our study revealed that physicians may weigh a host of socio demographic and clinical factors prior to making a CDS recommendation to PCa patients.Patients' acceptance of recommended CDS was potentially modifiable by certain sociodemographic factors.Physicians, especially urologists, should fully consider the hindrances behind patient's refusal of recommended CDS, thus improving patient-doctor shared decision-making, guiding patients toward the best alternative and achieving better outcomes.Further studies are necessitated to confirm the generality of our results.

Figure 2 .
Figure 2. Impact of surgical refusal on survival rate in unselected prostate cancer patients from SEER data base between 2010 and 2019.Shown are.(A) Kaplan-Meier curves of cancer-specific survival in patients with prostate cancers.(B) Kaplan-Meier curves of overall survival in patients with prostate cancers.(All p < 0.001) Abbreviations: CDSA = cancer-directed surgery accepted; CDSnA = cancer-directed surgery not accepted.

Table 1 .
Baseline comparisons between the patients with cancer-directed surgery recommended (CDSR) and not recommended (CDSnR) from the Surveillance, Epidemiology, and End Results (SEER) database.PSA, Prostate-specific antigen; PSM, propensity score matching.

Table 2 .
Factors related to physicians' recommendation of cancer-specific surgery without propensity score matching.PSA, Prostate-specific antigen.

Table 3 .
Baseline comparisons between the patients with cancer-directed surgery accepted (CDSA) and not accepted (CDSnA) from the Surveillance, Epidemiology, and End Results (SEER) database.PSA, Prostatespecific antigen; PSM, propensity score matching.

Table 4 .
Factors related to patients' refusal of cancer-specific surgery without propensity score matching.PSA, Prostate-specific antigen.